Exploring TRIO Gene’s Role in Autism and Schizophrenia

A study published in eLife has explored how rare mutations in the gene TRIO contribute to neurodevelopmental conditions by examining their effects in mice. The findings suggest that specific variants in this gene, which regulates proteins controlling the cytoskeleton, are associated with distinct changes in brain anatomy and behavior.

Investigating gene variants in neurodevelopmental conditions

TRIO encodes proteins that organize the cytoskeleton, a structural framework within cells. Mutations in TRIO have previously been linked with intellectual disability, autism spectrum disorder and schizophrenia. Despite this, the mechanisms through which these variants exert their influence on the brain have remained unclear.

To investigate this further, researchers introduced three TRIO variants, K1431M (autism-associated), K1918X (schizophrenia-associated) and M2145T (linked to bipolar disorder), into mice. These mice had one normal and one mutated copy of the gene, mimicking the genetic scenario observed in humans.

Brain volume and behavioral changes differ by variant

The study showed that mice with the K1431M and K1918X variants had smaller brains than control mice or those with the M2145T variant. This mirrored the reduced head circumference observed in some individuals with these mutations.

In motor coordination tasks, K1431M and K1918X mice performed worse than both M2145T and control mice. Although M2145T mice did not display motor deficits, further analysis revealed atypical neuronal signal processing.

Sex-based behavioral differences were also reported. Female K1431M mice showed increased anxiety when exposed to unfamiliar mice. M2145T females performed less well than males on memory-based object recognition tasks. These differences in behavior had not been described in earlier models and highlight the importance of studying genetic variations in living organisms.

Altered neuron signaling linked to Rac1 activity

The team found that each TRIO variant affected how neurons communicated. While most studies have focused on the receiving end of chemical signaling between neurons, this research revealed that TRIO mutations predominantly disrupted the release of signaling molecules.

One protein affected by TRIO activity is Rac1, a signaling molecule that contributes to cytoskeletal structure and neurotransmitter release. The study observed increased Rac1 activity in mice with the K1431M variant. This finding contrasted with earlier biochemical data suggesting reduced Rac1 activity and emphasized the value of animal models for understanding cellular behavior.

To test the functional consequences, brain tissue from K1431M mice was treated with a Rac1 inhibitor. This treatment successfully restored glutamate release, a key process in neuronal signaling.

Future directions focus on reversing behavioral effects

The results suggest that TRIO gene variants cause distinct cellular and behavioral outcomes, likely through changes in Rac1-mediated signaling. The research team is now exploring whether normalizing Rac1 activity can also improve behavioral outcomes in affected mice.

Reference: Ito-Ishida A. eLife Assessment: Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice. 2025. eLife. doi: 10.7554/eLife.103620.2.sa3

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